Abundant binary promoter switches in lineage-determining transcription factors indicate a digital component of cell fate determination
Hongchuan Li,
Md Ahasanur Rahman,
Michael Ruesch,
Caprice D. Eisele,
Erik M. Anderson,
Paul W. Wright,
Jennie Cao,
Shashikala Ratnayake,
Qingrong Chen,
Chunhua Yan,
Daoud Meerzaman,
Roshini S. Abraham,
Aharon G. Freud,
Stephen K. Anderson
Affiliations
Hongchuan Li
Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
Md Ahasanur Rahman
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
Michael Ruesch
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Medical Scientist Training Program, The Ohio State University, Columbus, OH 43210, USA
Caprice D. Eisele
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
Erik M. Anderson
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
Paul W. Wright
Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
Jennie Cao
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
Shashikala Ratnayake
Cancer Genomics and Bioinformatics Branch, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, MD 20892, USA
Qingrong Chen
Cancer Genomics and Bioinformatics Branch, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, MD 20892, USA
Chunhua Yan
Cancer Genomics and Bioinformatics Branch, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, MD 20892, USA
Daoud Meerzaman
Cancer Genomics and Bioinformatics Branch, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, MD 20892, USA
Roshini S. Abraham
Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 43210, USA; Department of Pathology, The Ohio State University, Columbus, OH 43210, USA
Aharon G. Freud
Department of Pathology, The Ohio State University, Columbus, OH 43210, USA
Stephen K. Anderson
Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Corresponding author
Summary: Previous studies of the murine Ly49 and human KIR gene clusters implicated competing sense and antisense promoters in the control of variegated gene expression. In the current study, an examination of transcription factor genes defines an abundance of convergent and divergent sense/antisense promoter pairs, suggesting that competing promoters may control cell fate determination. Differentiation of CD34+ hematopoietic progenitors in vitro shows that cells with GATA1 antisense transcription have enhanced GATA2 transcription and a mast cell phenotype, whereas cells with GATA2 antisense transcription have increased GATA1 transcripts and an erythroblast phenotype. Detailed analyses of the AHR and RORC genes demonstrate the ability of competing promoters to act as binary switches and the association of antisense transcription with an immature/progenitor cell phenotype. These data indicate that alternative cell fates generated by promoter competition in lineage-determining transcription factors contribute to the programming of cell differentiation.
